A STUDY  OF  THE  HOESCH  REACTION 


BY 

WILSON  DAVIS  LANGLEY 

B.S.  Wesleyan  University,  1918 
M.S.  Wesleyan  University,  1919 


THESIS 

SUBMITTED  IN  PARTIAL  FULFILLMENT  OF  THE  REQUIREMENTS 
FOR  THE  DEGREE  OF  DOCTOR  OF  PHILOSOPHY  IN  CHEMISTRY 
IN  THE  GRADUATE  SCHOOL  OF  THE  UNIVERSITY 
OF  ILLINOIS,  1922 


URBANA,  ILLINOIS 


Digitized  by  the  Internet  Archive 
in  2015 


https://archive.org/details/studyofhoeschreaOOIang 


\ 0 u,  u, 

k)  & (o 


c 

UNIVERSITY  OF  ILLINOIS 

THE  GRADUATE  SCHOOL 

„.May  i<u  2 

I HEREBY  RECOMMEND  THAT  THE  THESIS  PREPARED  UNDER  MY 

SUPERVISION  by JUson  Pavls  Langley 

ENTITLED A STUDY  03?  THE  HOflSCH  REACTION . 


BE  ACCEPTED  AS  FULFILLING  THIS  PART  OF  THE  REQUIREMENTS  FOR 
THE  DEGREE  OF Docljor  .of.  .Philosophy  _in_  Chemistry. 


Recommendation  concurred  in* * 


UTft  ij\  . »<, 


Y/r-  ^>- 


*Required  for  doctor’s  degree  but  not  for  master’s 


Committee 

on 

Final  Examination* 


*.>  t 


The  writer  feels  a deep  sense 
of  gratitude  to  Professor  Roger  Adams 
for  his  willing  and  patient  guidance 
during  three  years  at  the  University 
of  Illinois,  and  in  particular,  for 
his  direction  in  this  research  wor£. 


I. 

i . 

TABLE  OF  CONTENTS. 

INTRODUCTION.  Page 

1. 

II. 

HISTORICAL. 

3. 

III. 

THEORETICAL • 

10.  ! 

1 IV* 

A discussion  of  the  results  obtained  in  the 
condensation  of  nitriles  with  phenols. 
EXPERIMENTAL  . 

15. 

A.  PREPARATION  OF  NITRILES. 

1.  Ethylene  cyanhydrin. 

15. 

2.  fi -chlorpropionitrile . 

15. 

3.  Acrylic  nitrile. 

17. 

4.  y -chlorbutyronit rile . 

18. 

B.  CONDENSATIONS  OF  NITRILES  WITH  RESORCINOL. 

1.  Ethylene  cyanhydrin  with  resorcinol. 

19. 

2.  '/£>-cyanethyl  acetate  with  resorcinol. 

20. 

3.  y-chlorpropionitrile  with  resorcinol. 

21. 

Isolation  of  intermediate  product. 

23. 

Derivatives  of  2-4 -dihydroxy 'jS-phenyl 
propionic  acid. 

24. 

Preparation  of  umbelliferone . 

29. 

Reduction  of  umbelliferone. 

29. 

4.  Acrylic  nitrile  with  resorcinol. 

5.  y -chlorbutyronitrile  with  resorcinol. 

31-  j 

Isolation  of  intermediate  products. 

33. 

C.  CONDENSATIONS  OF  NITRILES  WITH  RESORCINOL- 

MONOMETHYL  ETHER. 

1.  jB-chlorpropionit rile  with  resorcinol- 

monomethyl  ether. 

33. 

ii. 

D.  CONDENSATION  OF  NITRILES  WITH  ORCINOL. 

^-chlorpropionitrile  with  orcinol.  36. 

E.  CONDENSATION  OF  NITRILES  WITH  PHLOROGLUCINOL . 

1.  '^--chlorpropionit rile  with  phloroglucinol.  37. 

E.  Acrylic  nitrile  with  phloroglucinol.  39. 

3.  'y-chlorbutyronit  rile  with  phloroglucinol.  40. 


F.  OTHER  CONDENSATIONS  ATTEMPTED. 

1.  Halogen  compounds  with  resorcinol.  40. 

E.  ^-chlorpropionitrile  with  phenol.  41. 

3.  P-chlorpropionitrile  with  E-4-dihydroxy 

/3-phenylpropionic  acid.  41. 

V.  SUMMARY.  41: 

VI.  BIBLIOGRAPHY.  43. 


1. 


The  condensation  of  phenolic  compounds  with  nitriles 
has  been  carried  out  under  different  conditions,  and  occurs  in  two 
ways,  depending  upon  the  nature  of  the  nitriles.  The  products  ob- 
tained have  been  either  ketones  or  lactones,  and  so  far,  little 
work  has  been  done  to  determine  the  factors  which  influence  the 
condensation  to  give  one  or  the  other  type  of  compound.  It  was 
thought  by  the  writer  that  a study  of  the  Hoesch  reaction,  the 
condensation  of  nitriles  with  phenols  by  means  of  dry  hydrogen 
chloride,  which  gives  either  ketones  or  lactones,  would  help  to 
explain  the  nature  of  the  condensation. 

By  the  use  of  certain  halogen  substituted  nitriles 
it  ought  to  be  possible,  if  compounds  of  a ketonic  nature  are  ob- 
tained, to  synthesize  some  important  products  which  are  found  in 
nature,  or  which  are  obtained  from  natural  products  by  chemical 
trans for  nation.  This  can  be  seen  from  the  theoretical  equation: 


+ h2o 


HC1 

MC.CH_.CH  Cl  

£ 2 


OH 

C.CH2CH2C1 


^ HOf'NoH 

k^C.CHp.CHg.Cl 

MH 

( w -chlor  respropiophenone  ) 


Upon  treatment  of  the  ketone  with  a weakly  basic  substance  such  as 
pyridine  or  sodium  bicarbonate,  the  halogen  atom  should  split  out 
as  hydrochloric  acid,  as  in  the  following  scheme  : 


HOr^.  OH 

I^JC.CHg.CH  Cl  + MaHCOg 


NaCl  +•  C0£+  H£0  . 


The  7-oxychromanone  farmed  could  be  converted  by  well  known  reactior 
into  the  following  compounds: 


3 


ho/Yj"chp  ho^V°n;h  ho  A oh 

kJL  ^C:NUH  l L/C.  OH  LJcO.CHo.OH 

C:0  ^C:0  Fisetol. 


* 


. 


. 

f 

2. 


the  second  and  third  of  which  have  been  isolated  from  the  decomp- 
osition products  of  braselin  (1)  and  fisetin  (2) 

(1)  HO  ry0'?O8g  (2> 

Uv°-0H 

§ 

HO  OH 


but  which  have  never  been  synthesized.  By  the  use  of  y-chlorbutyro- 

nitrile  (Cl.  CHg.  CHg.  CHg.  CIO,  it  ought,  theoretically,  to  be  possible 

to  isolate  the  corresponding  chlorket one  s , and  to  prepare  seven 

membered  ring  systems  corresponding  to  the  ehromanones.  By  the  use 

of  ethylene  eyanhydrin  (HO.CHp.CH  .CN),  it  should  be  possible  to 

^ d 

synthesize  a homologue  of  fisetol  HOi^iOH 

Ks  C. CHg. CHgOH.  This  compound, 

6 

because  of  the  longer  side  chain,  should  be  more  stable  than,  but 

should  have  chemical  properties  similar  to  those  of  fisetol  itself. 

This  nitrile  would  also  be  a means  of  preparing  the  compounds  which 

are  derived  from  /3-chlorpropionitrile  with  phenols,  as  the  hydroxyl 

group  ought  to  be  readily  replaceable  by  halogen,  or  removed  in  the 

form  of  water,  by  closure  of  the  ring  to  give  7-02y ehromanone. 

If,  on  the  other  hand,  the  Hoesch  reaction  should  go 

abnormally  in  the  case  of  these  nitriles,  it  ought  to  be  possible 

through  the  following  mechanism; 

HO  OH  HCP^OH  HC1  ^ 

Ky  + Cl.  CHg.  CHg.  CK  ► kyCEg.CHgCN  H2U 

HOf^i  uH 

k/CH2.CHo.C00H  UH4CI 


to  synthesize  certain  phenolic  acid  3 which  have  been  hitherto 
unknown  or  difficult  to  prepare.  In  addition,  it  ought  to  be 
possible  to  prove  beyond  doubt  the  mechanism  of  the  Hoesch  reactior 


. 


. 


. 


For  instance,  if,  as  is  assumed  by  one  author,  the  halogen  of  the 
chlorimido  group  (R.CC1:RH)  reacted  with  the  phenolic  hydroxyl 
group,  there  might  be  obtained  an  ester  of  chlorpropior.ic  acid, 
(Cl.CHp.CH  .COOR),  or,  if  the  P-halogen  then  reacted,  the  lactone  of 
a phenolic  acid.  If,  on  the  other  hand;  the  halogen  in  the  ^or  y 
positions  of  the  nitrile  reacted  first,  it  should  be  possible  to 
isolate  the  corresponding  nitrile  or  amide  of  the  acid. 

It  would  be  of  value  also  to  determine  whether  or  not 
the  aliphatic  unsaturated  nitriles,  such  as  acrylic  nitrile  (CH^: 
CH.CR)  react  in  a manner  similar  to  the  aromatic  unsaturated  nitrile 
such  as  cinnamic  nitrile,  and  p-coumaric  nitrile,  used  by  Fischer 
and  Rouri  in  their  attempt  to  synthesize  flavones  by  means  of  the 
Hoesch  reaction. 

II.  HISTORICAL. 

The  first  condensation  of  a nitrile  with  a phenol  was 

( 3 ) 

accomplished  by  Bistrzycki  , who  condensed  mandelic  nitrile  and 
soma  of  its  derivatives  with  phenols  by  means  of  73 % sulphuric  acid, 
and  obtained  a mixture  of  acids  and  lactones.  The  nitrile  was  used 
in  place  of  mandelic  acid  to  determine  whether  or  not  it  would  give 
an  increased  yield  of  lactone  over  that  of  the  corresponding  acid, 
and.  it  was  found  that  with  the  nitrile,  the  yield  of  lactone  was 
39-43%,  and  of  the  acid  15%,  while  wit  h ' mand  elic  acid,  the  amount 
of  lactone  was  32%,  and  of  the  acid  39%.  Simonis1 4 Hhen  prepared  a 
numuer  of  lactones  from  mandelic  acid  and  ^-naphthol,  using  mandelic 
acid  instead  of  the  nitrile  because  it  was  easier  to  prepare.. 


3 


' 


r 


. 


4. 


Dimroth^j  in  1902  discovered  that  when  benzanilide- 
imidochloride  reacted  with  dimethyl-aniline,  there  v/as 

V_/  vv  /n.ju(ch3j2 

obtained  the  phenyl- imine  of  dime thyl- aminobenzophenone  l 
and  that  when  formaldehyde- anil ine  (CgHgNE.CHO)  was  condensed  with 
phenols  by  means  of  phosphorus  oxychlorid e in  dry  ether,  there  v/as 
obtained  an  anilide,  which  on  warming  with  dilute  alkali  hydrolyzed 
to  the  corresponding  aldehydes.  The  condensation  was  explained  in 


the  following  manner: 
*NH.  CHO 

+ P0C1, 


0 


:CHC1 


o 


+ 


H3P04 


It  was  found  that  the  anils  separated  from  the  reaction  mixtures  as 
hydrated  compounds,  and  they  were  assigned  a structure  accordingly 


HO/NOH 

l^jCHOH.NH^ 


Dimroth  also  condensed  formaldehyde  aniline  with  pyro- 
gallol  ( 1-2-3-trihydroxybenzene  ) obtaining  a 70%  yield  of  the  alde- 
hyde, which  showed  that  the  hydroxyl  groups  could  occur  in  positions 
other  than  meta  to  each  other.  This  reaction  was  a forerunner  of 
the  Gatterman  method  for  the  synthesis  of  phenolic  aldehydes. 

Meyer  obtained  what  he  believed  to  be  3-oxyflavone 

0; 

” "CHgCN 

with  resorcinol  by  means  of  dry  hydrogen  chloride.  The  mechanism 
proposed  by  him  for  the  reaction  was  as  follows: 


> 


5. 


H°Q°H+  V g.  C6H6 


K C' 

Enol  form. 


+ HH  + 
3 


8 H2°- 


HOr^O-O.C.H-  HO  |^>U-C.C,Hc 

U PH  6 51-  hh4ci  [ XJa  6 5 

HOOC  " 


c 

V9 

0 


H2°. 


Unfortunately,  the  details  of  the  experiment  are  not  given,  nor 
definite  proof  of  the  structure  of  the  compound  obtained.  Sonn  latex 
repeated  the  work,  and  proved  that  the  compound  isolated  by  keyer 
was  not  a flavone , but  7-oxy  /2-phe(hyl  counarin.  The  mechanism  was 


therefore  incorrect,  as  given  by  Meyer,  and  should  have  been 
. /H  ,NH 

C-CHCN  X _ UHpCN 

2 + HC1  * C H5  Cl 


C6H5 


NC 


HO/NOH  CHp 

i J -f-  Cl.C.NHp 

W 


H0/N0H 


KC 

CH 

C6H5 


HCi 


HO 


(X 


9 :NE.HC1 


h2o- 


HOrOr^CiO 


^C6H5 


.1  7i 


NH^Cl 


The  Gatterman  synthesis  of  aldehydes  by  the  conden- 
sation of  phenols  and  hydrocyanic  acid  in  dry  ether  solution  by 
means  of  dry  hydrogen  chloride  was  discovered  in  19u7.  The  mechan- 
ism of  this  reaction  is  generally  accepted  as  being  the  addition  of 
hydrogen  chloride  to  the  nitrile,  and  a condensation  of  the  chlor- 
imide  formed  with  the  phenol.  On  the  hydrolysis  of  the  aldimide 
obtained,  an  aldehyde  is  formed. 

HC1 

^ HU  :CH  HO/NoH 

Cl  l JCH  H20-^ 


HOQOH  + 


U =-GH 


HO/NOH 

NH.HC1 


HOi^XOH  + 

L^Jcho 


mh4ci 


/ ■ 


6 . 

Hoesch^8^,  in  seeking  to  extend  the  Gatterman  aldehyde 
synthesis  to  the  preparation  of  ketones,  generalised  the  condensa- 
tion of  nitriles  with  phenolic^ compounds , and  from  that  time  the 
reaction,  when  applied  to  the  synthesis  of  ketones,  has  been  known 
as  the  Hoesch  reaction.  It  happened  that  in  this  work  nitriles  were 
used  which  gave  only  ketones,  and  Hoesch  proved  that  acetonitrile 
( CH^CU ) and  benzonitrile  ( CgHgCN ) could  be  used  with  dihydroxy  phei 
-ols  with  the  hydroxyl  groups  in  the  meta  position  to  each  other. 
The  mechanism  for  the  reactions,  as  given  by  Hoesch,  is  similar  to 
that  for  the  Gatterman  aldehyde  synthesis,  a ketimide  being  formed 
instead  of  an  aldimide. 

HO/NOH  HG1 


-f-  CH^CN 


HO/NOH 

I Jc  . CH/t  + HpO 
HC1 


HO/XOH 

]c . ch3 


hk4ci. 


Evidence  for  the  formation  of  an  intermediate  addition  compound 
between  hydrochloric  acid  and  nitriles  has  been  given  by  Trbger 

( Q ) 

and  Liining  , who  isolated  and  proved  thex addition  product  of 

hydrochloric  acid  and  chloracetonitrile  ( Cl>.  CHg.  CH  ) to  be  monochlor 

-acetimide  chloride  ( Cl. CHg. CC1 :NH ) . 

Later,  Hoesch  synthesized  maclurin  L J C<(  yOH  , a 

OH  0W 

product  found  in  yellow  wood,  or  Morus  tinctoria,  by  the  condense- 

tion  of  phloroglucinol  and  protocatechuic  nitrile  k /OH  , and 

1 — CH 

also  made  the  related  compound  from  resorcinol  and  vanillic 
/ — 'pCK'z 
nitrile  HC<^J>0ir. 

Ghosh^u^  condensed  benzoyl  acetonitrile  ( C^H^CO . CHg. CN 
formyl  acetonitrile  ( OHC . CHg. CN ) , and  other  nitriles  with  phenols, 
using  as  condensing  agents  sulphuric  acid,  hydrochloric  acid, 
phosphorus  oxychloride,  and  zinc  chloride.  He  gives,  for  instance. 


. 


. 


■ . 


- 


7. 

the  condensation  of  resorcinol  and  acetyl  phenyl-aceto  nitrile 

HSO, 


( CHg. CO.CHC^E^. CN ) , the  following  mechanism: 

.0 


HO^OH  HO.C.CH*  HO.^Y^C.CH* 

kj  ^ NC.5.C6H5  * _'K2S04  ^^^Nh"6115 

2 


,.cn3 

/C.C.H, 


Enol  form 

Jj’or  the  synthesis  of  a flavone  , he  used  resorcinol  and  benzoyl 
acetonitrile,  and  explained  the  reaction  as  follows: 


HO^OH  HO.C.C.H 


u + 


NC . CH 


6 5 


H0^V°'C.C6H5 


uj;  ” -v-TX^6'5 


7-oxyflavone . 

He  proved  the  structure  of  his  compounds  by  decomposing  them  with 
alkali  and  isolating  the  products  formed,  and  confirms  their  struc- 
ture by  showing  that  they  gave  colored  salts,  and  therefore  must 
have  a quinonoid  structure.  In  view  of  the  work  done  by  Sonn,  which 
proves  that  the  mechanism  given  by  Meyer  for  the  condensation  of 
the  imide  of  benzoyl  acetonitrile  with  resorcinol  is  incorrect,  it 
must  be  concluded  that  the  factor  which  determines  the  mechanism 
of  the  condensation  is,  as  is  given  by  Ghosh,  the  complexity  of  the 
substituent  on  the  carbon  atom  of  the  esters  or  nitriles  used, 
the  larger  groups  inhibiting  enolization.  In  confirmation  of  this 
theory,  it  is  pointed  out  that  ethyl  acetoacetate  with  phenols 
gave  only  cournarins,  while  ethyl  ethyl  acetoacetate  gave  a mixture 
of  the  cournarins  and  y-pyrones,  and  benzyl  ethyl  acetoacetate  gave 
only  the  y-pyrones. 

Sonn*^  ^observed  that  the  nitrile  which  Meyer  used  was 
readily  hydrolyzed  by  shaking  with  cold  mineral  acids,  giving 
benzoyl  acetonitrile,  and  that  the  hydrolysis  product  corresponded 


. 


. 


8. 


( 12  ) 

to  the  nitriles  used  by  Bargellini  and  Horli-Horti  , in  having 
the  structure  H.CO.CHg.CN.  These  investigators  condensed  nitriles 
having  this  structure  with  phenols,  and  isolated  a number  of  lac- 
tones and  acids.  The  condensation  depends  upon  the  enolization  of 
the  hydrogen  of  the  methylene  group  to  give  a compound  of  the  type 
fi. COH: CH. CU.  Sonn  used  the  acyl  compound  obtained  by  the  hydrolysis 
of  the  imide  of  benzoylacetonitrile  in  repeating  and  extending  the 
work  of  Ale  ye  r. 

In  using  saturated  aliphatic  nitriles,  Sonn  was  able  to 

secure  normal  ketone  condensation  by  means  of  the  Hoesch  reaction. 

It  is  important  to  note  that  he  used  chloracetonitrile  (CI.GH^.CNJ, 

and  obtained  a normal  condensation  with  resorcinol,  u>-chlor-resacetc 

phenone  being  isolated.  This  was  unstable  to  alkali,  and  when  an 

attempt  was  made  to  replace  the  halogen  with  a hydroxyl  group,  the 

ring  closed  to  give  6-oxycumaranone . This  work  was  done  to  find  a 

method  for  the  preparation  of  fisetol. 

1 13 ) 

Slater  and  Stephen  also  attempted  to  synthesize  fisetol 

and  some  related  compounds  by  means  of  the  Hoesch  reaction,  using 

hydroxy  acetonitrile  and  acetaldehydecyanhydrin , and  while  a normal 

ketone  condensation  occurred,  they  were  unable  to  obtain  the  desirec 

compounds  due  to  the  closure  of  the  ring  to  give  cuhb. ranone s . 

They  also  made  similar  compounds  by  the  use  of  phloroglucinol  in 

(14  ) 

place  of  r eso rcinol.  Stephen  later  substituted  cinnamanilide- 
imidochloride  ( C^H^. CH:CH. CC1 :UCgHg ) and  chloracet imidochloride 
for  the  nitriles,  and  found  that  neither  hydrochloric  acid  nor  zinc 
chloride  were  necessary  to  bring  about  a condensation,  and  that  the 
best  yields  of  product  were  obtained  when  the  reaction  mixture  was 


' 


• ; 


9. 


heated.  This  led  him  to  advance  a theory  regarding  the  mechanism 

of  the  reaction  differing  from  that  of  ^oesch.  This  theory  involved. 

the  reaction  of  the  halogen  of  the  imidochloride  with  the  hydrogen 

of  the  phenolic  hydroxyl  followed  by  a rearrangement  into  the  ring, 

which  rearrangement  occurred  best  with  heating.  No  intermediate 

products  were  isolated  to  which  could  be  assigned  an  ether  linkage. 

This  mechanism  resembles  the  rearrangement  of  the  allyl 

phenyl  ethers  to  o-ally  phenols,  which  was  discovered  by  Claisen  . 

(16) 

Adams  and  Powell  have  shown  conclusively  that  many  unsaturated 
groups,  some  of  which  are  more  reactive  chemically  than  the  allyl 
group,  could  not  be  rearranged  into  the  ring  upon  heating  for  many 
hours.  Therefore  it  is  unreasonable  to  expect  that  the  mechanism 
of  the  Hoesch  reaction,  which  is  applicable  to  a great  number  of 
phenols  and  nitriles  can  be  explained  in  this  way. 


phloroglucinol,  and  found  that  no  ketonic  condensation  tofck  place. 
Apparently  they  attempted  to  synthesize  flavones  by  the  Hoesch 
condensation,  but  due  to  the  unsaturated  nature  of  the  nitriles, 
only  lactones  were  obtained.  They  did  not  suggest  a mechanism  for 
the  reaction  other  than  the  addition  of  the  phenol  to  the  double 
bond,  and  the  simultaneous  closing  of  the  ring  to  give  a lactimide. 
However,  when  they  used  p-hydroxy  -phenyl propionitrile , in  which 
case  there  was  no  unsaturated  carbon  atom  in  the  side  chain  to 


react  with  the  phloroglucinol,  they  were  able  to  secure  normal 


( 18 ) 

Fischer  and  ^ouri  condensed  cinnamic  nitrile  ( 


CHiCH.CN)  and  p-hydroxyc oumar ic  ni 


trile  IIO^ 


CH: GH. CN  with 


condensation,  and  isolated 


Bauer  and  Schoder  condensed  cyanacetic  ester  with 


. 


lu 


resorcinol  by  neans  of  the  Hoesch  reaction,  and  obtained  in  this 


also  obtained  the  compound  having  the  structure  HC  /OH, 

HO  JC  . OH 

for  Aarrer  found  that  the  compound  of  the  structure 


HOOC.CH:CHf/N1 C . CH*  (17  > 

HO 

could  not  be  made  to  close  into  the  lactone,  or  coumarin  derivative. 


It  has  been  found  tha  t |3>-chlorpropionitriie , y -chlor- 
butyronitrile , and  acrylic  nitrile  all  condense  with  phenols  to  give 
nitriles,  or  intermediates  which  upon  hydrolysis  give  lactones  or 
acids,  and  that  in  no  case  is  a ketone  formed,  ethylene  cyanhydrin 
has  been  shown  not  to  condense  at  all  with  phenols,  except  to  give 
a snail  amount  of  2-4-dioxy -phenylpropionic  acid,  the  formation 
of  which  is  undoubtedly  due  to  the  replacement  of  the  hydroxyl  of 
the  nitrile  by  chlorine  from  hydrochloric  acid,  and  the  reaction  of 
the  resulting  chlorpropionitrile  with  the  phenol 

In  the  case  of  resorcinol  and /3-chlorpropionitrile , a 
solid  intermediate  product  was  obtained,  which  was  a hydrochloride 
of  a nitrogen  containing  compound.  While  the  halogen  analysis  did 
not  lead  to  a definite  formula  for  this  substance,  on  treatment  with 
water,  the  nitrogen  and  halogen  were  instantly  removed,  and  there 
was  obtained  the  lactone  of  2-4-dioxy  0-phenyl  propionic  acid.  This 
leads  to  the  conclusion  that  the  solid  had  the  structure 


way  4-7-dioxycoumar in  HO 


it  is  significant  that  they 
>0  n 

^C:0 


III.  THEORETICAL. 


' 


s 


. 


11. 


Were  it  of  another  structure,  the  hydrolysis  to  the  lactone  would 
take  much  longer,  for  the  reaction  of  nitriles  and  amides  with  wafca 
is  comparatively  slow,  it  could  not  have  the  structure  of  an  open 
chain  propionic  acid  derivative,  for  then  the  ring  could  not  have 
closed  on  treatment  with  water  to  give  the  lactone  obtained.  Howeve 
the  isolation  of  this  compound  does  not  prove  whether  it  was  the 
/3-halogen  atom  or  the  halogen  of  the  chlorimide  that  reacted  first 

The  fact  that  acrylic  nitrile  gave  the  same  lactone  as 

/3-chlorpropionitrile  shows  that  it  adds  hydrochloric  acid  to  give 

/3-chlorpropionitri le , and  that  this  compound  condenses  with  the 

phenol.  The  addition  of  hydrobromic  acid  to  acrylic  nitrile  has 

( 20 ) 

been  shown  by  Moureu  to  be  practically  instantaneous,  and  this 
is  the  only  way  that  the  saturated,  halogen  free  lactone  which  is 
obtained  can  be  explained.  This  mechanism  also  explains  the  abnor- 
mal behaviour  of  the  compounds  condensed  by  Fischer  and  houri.  It 
has  been  shown  by  these  workers  that  p-hyd roxyphenyl  propionitrile 
which  does  not  permit  of  a halogen  replacing  a hydrogen  of  the 
propionic  residue,  condenses  normally  with  phloroglucinol . 

The  isolation  of  2-oxy-4-methoxy  '/S-phenyl  propionitrile 


ether  with  /3  -chlorpropioni trile  is  proof  of  the  hypothesis  that 
it  is  the  chlorine  attached  to  the  /3-carbon  atom  that  condenses 
first  with  the  phenol,  and  that  it  condenses  in  a position  ortho 
to  a phenolic  hydroxyl  group.  Other  nitrogen  compounds  have  been 
obtained  as  inte mediates , expecially  in  the  case  of  ,y-chlorbu- 
tyro  nitrile,  which  intermediate  hydrolyzed  slowly  on  treatment  wi 
water,  in  marked  contrast  to  the  rapid  hydrolysis  of  the  hydro- 
chloride of  the  imide  obtained  with  resorcinol. 


r 


r 


' 


■ 

* 

12. 


It  has  been  shown  that  a small  amount  of  water  prevents 
the  Hoeach  condensation  from  talcing  place.  This  was  clearly  shown 
in  an  attempt  to  condense  2-d-dioxy  /3-phenyl  propionic  acid  with 
/3-chlorpropionitrile , when  a mixture  of  the  original  acid  and  of 
its  lactone  were  obtained,  but  no  trace  of  a condensation  product. 

It  was  also  shown  when  an  attempt  was  made  to  condense  phloroglu- 
cinol  containing  water  of  crystallization  with  /3-chlorpropionitrilo 
when  a viscous,  brown,  heavy  liquid  was  isolated  instead  of  the 
crystalline  lactone  or  aoid.  While  this  liquid  possessed  some  of 
the  properties  of  a lacione,  it  could  not  be  purified.  It  is  prob- 
able that  in  this  case  the  zinc  chloride  removed  enough  of  the  water 
of  hydration  to  enable  a portion  of  the  products  to  condense,  but 
that  other  impurities  which  formed  prevented  the  isolation  of  the 
desired  compounds. 

It  has  been  proved  that  although  the  halogen  atom  of 
the  yS  or  y chlomitriles  react  abnormally  in  the  Hoesch  condensation, 
halogens  in  compounds  other  than  nitriles  do  not  react  at  all.  It 
is  probable  that  the  nitrile  group  activates  the  halogen  atom  suf- 
ficiently to  bring  about  the  condensation,  whereas  in  the  case  of 
other  compounds,  such  as  trine thylene  bromidie,  or  ethylene  dibrom- 
ide, the  halogen  is  too  inactive  to  condense.  While  it  might  be 
expected  that  the  halogen  in  /3-chlorpropionit rile  is  less  reactive 
than  in  /3-chlorpropionic  ester,  the  failure  of  the  latter  to  con- 
dense is  probably  due  to  a splitting  of  the  ester  by  the  zinc 
chloride  and  hydrochloric  acid,  with  the  formation  of  enough  of 
side  products  to  inhibit  the  reaction.  Likewise,  it  might  be 
expected  that  since  ethylene  cyanhydrih  did  not  react  because  of  the 
presence  of  the  free  hydroxyl  group,  the  acetate  of  ethylene  cyan- 


-40  U 


ib 


hydrin  would  react,  But  the  acetate  also  failed  to  condense. 

Furthermore,  it  has  been  shown  that  condensation  of 
halogen  substituted  nitriles  does  not  occur  with  phenol. 

It  might  be  supposed  that  in  the  case  of  the  halogen 
substituted  nitriles,  hydrochloric  acid  first  split  out,  leaving 
an  unsaturated  nitrile  which  would  condense  with,  or  add  to  the 
phenol.  But  three  reasons  militate  against  this  hypothesis.  First; 
acrylic  nitrile  does  not  condense  with  phenols  until  hydrochloric 
acid  is  passed  into  the  solutions  If  the  unsaturated  nitrile  were 
the  reactive  reagent,  hydrochloric  acid  should  be  unnecessary  for 
the  condensation.  Second;  the  halogen  of /3-chlorpropionitrile  is 
not  so  unstable  that  it  would  split  out  in  the  presence  of  a sat- 
urated ethereal  solution  of  hydrochloric  acid  to  give  an  unsaturatec. 
nitrile.  The  ready  addition  of  hydrobromic  acid  to  acrylic  nitrile 
substantiates  this  reason.  Third;  in  the  case  of  the  condensation 
fif  '/-chlorbutyronit rile , it  might  be  expected  that  instead  of  the 
y -substituted  acid,  a ^-subst i tuted  acid  would  result,  as  in  the 


The  acid  formed  would  then  in  all  probability  give  a lactone  as 
readily  as  £-4-dioxyy5-phenylpropionic  acid.  But  the  acid  obtained 
does  not  form  a lactone  on  heating,  and  the  intermediate  obtained 
in  the  condensation  is  not  in  the  form  of  a lactone  imtde  hydro- 
chloride, since  it  is  fairly  stable  to  water,  and  does  not  give  a 
lactone  on  hydrolysis. 

The  difference  in  the  behaviour  of /3-chlor,  and  y-chlor 
nitriles  from  chloracetoni trile  in  their  condensation  with  phenols 


sch< 


14. 

by  means  of  the  Hoesch  reaction  is  attributed  to  the  peculiar 
reactivity  of  the  /3  and  y halo  gen  atoms.  In  the  same  sense,  the  reac- 
tivity  of  the  hydroxyl  group  in  ethylene  cyanhydrin,  or  the  ease 
with  which  it  is  eliminated  in  the  form  of  water  explains  the  fail- 
ure of  that  nitrile  to  react  with  phenols,  whereas  the  acetaldehyde 
cyanhydrin  reacted  to  give  a normal  condensation. 

Resorcinol  monomethyl  ether  reacts  with  nitriles  very 
much  more  slowly  than  resorcinol  itself,  but  there  is  little  dif- 
ference in  the  rate  of  reaction  of  resorcinol,  orcinol,  and  phlor- 
oglucinol.  It  has  been  shown  that  hydrogen  chloride  adds  on  to  the 
nitrile  group  comparatively  slowly,  for  in  the  case  of  the  resorcin- 
ol monomethyl  ether,  the  nitrile  was  obtained  from  an  ether  solution 
which  had  been  saturated  for  several  days  with  hydrogen  chloride. 

Had  hydrogen  chloride  added  to  the  nitrile  group,  there  is  no 
reason  to  supppse  that  the  ring  would  not  have  closed  to  give  a 
lactimide  just  as  occurred  in  the  condensation  of  resorcinol  itself. 
The  lactimide  that  was  formed  in  the  reaction  was  thrown  out  of  the 
ether  in  the  form  of  an  oil  or  mixture  of  oil  and  crystals,  and 
upon  hydrolysis  gave  a mixture  of  the  lactone  and  acid. 


. 


- 


15. 

IV.  EXPERIMENTAL. 

A.  PREPARATION  OF  NITRILES. 

1.  Preparation  of  ethylene  eyanhydrin. 

1285  grams  of  ethylene  chlorhydrin  were  dissolved  in  2 
liters  of  95 °/o  alcohol  and  heated  to  boiling  in  a 5-1.  round  bottom 
flask  under  an  efficient  reflux  condenser.  The  flask  was  maintained 
at  boiling  temperature  while  there  was  added  through  a dropping 
funnel  a saturated  solution  of  785  grams  of  sodium  cyanide  in  watei , 
the  addition  requiring  11/2  hours.  A more  rapid  addition  of  the 
sodium  cyanide  was  found  to  cause  vigorous  boiling,  so  that  the 
reaction  could  not  be  controlled.  The  mixture  was  refluxed  for 
twenty  hours,  during  which  time  a heavy  precipitate  of  sodium  chlor- 
ide was  formed.  The  alcohol  was  then  distilled  off  at  atmospheric 
pressure,  and  the  water  distilled  under  25-3u  mm.,  the  sodium  chloi 
-ide  which  separated  being  filtered  off  when  bumping  became  too 
great.  When  all  the  water  had  been  removed,  the  temperature  rose 
rapidly.  The  last  200  cc.  of  water,  which  boiled  higher  than  the 
main  portion  was  saved  separately,  and  fractionated  once.  About 
20  g.  of  ethylene  eyanhydrin  was  thus  recovered  and  added  to  the 
main  portion.  The  ethylene  eyanhydrin  was  then  distilled,  the 
fraction  boiling  from  117-120°  at  20  mm.  being  collected.  The  yield 
was  755  g.  or  66°/o  of  the  theory.  Boiling  point  at  atmospheric 
pressure  was  220°. 

2.  Preparation  of  ^-chlorpropionitrile . 

In  a dry  liter  Claisen  flask  were  placed  45o  g.  of 


. 


, 


16. 


powdered  c.p.  phosphorus  pentachloride . Over  it  were  poured  200  cc. 
of  dry  toluene.  A thermometer  was  then  placed  in  position,  and  over 
the  side  arm  of  the  flask  was  placed  an  ordinary  distilling  flask, 
so  that  air  could  he  drawn  through  it  at  atmospheric  pressure,  to 
carry  away  fumes  of  hydrochloric  acid,  'i'he  flask  was  cooled  in  an 
ice  bath,  while  145  g.  of  ethylene  cyanhydrin  were  added  through 
a dropping  funnel.  The  addition  was  at  such  a rate  that  no  phos- 
phorus oxychloride  distilled  over,  and  took  1 1/2  hours.  The  mix- 
ture was  stirred  frequently  during  the  addition,  care  being  taken 
that  there  was  no  accumulation  of  the  cyanhydrin  in  the  toluene, 
for  a sudden  reaction  would  then  be  likely  to  occur,  accompanied 
by  boiling  and  frothing,  which  would  cause  a violent  evolution  of 
hydrogen  chloride,  with  consequent  loss  of  product.  When  all  the 
ethylene  cyanhydrin  was  added,  the  flask  was  connected  to  a low 
vacuum  (25-30  mm. ) with  a water  trap  between  the  flask  and  the 
pump  to  catch  fumes  of  hydrogen  chloride  which  came  off  at  the 
beginning  of  the  distillation.  The  mixture  of  toluene  and  phos- 
phorus oxychloride  was  distilled  off  on  a water  bath.  This  heating, 
besides  removing  these  substances,  brough  the  reaction  to  comple- 
tion. When  most  of  the  toluene  and  phosphorus  oxychloride  were 
removed,  the  temperature  rose  slowly,  the  fraction  coming  over 
between  50-65°  at  20ram.  being  collected  separately  and  redistilled. 
The  lower  boiling  portion  was  discarded,  and  the  fraction  which 
came  over  between  65-72°  was  combined  with  the  main  portion  of 
nitrile  and  distilled  with  it.  The  fraction  which  boiled  from 
65-72°  was  fairly  free  of  phosphorus  oxychloride,  and  was  poured 
carefully  into  about  200  cc.  of  water,  so  that  the  mixture  did 


t 


17. 

not  become  warm  due  to  the  decomposition  of  the  phosphorus  oxy- 
chloride present.  If  the  mixture  were  allowed  to  heat  up,  a consid- 
erable portion  of  the  nitrile  would  become  hydrolyzed  and  lost. 

The  nitrile  was  separated  from  the  water,  washed  with  a solution 
of  sodium  carbonate,  again  with  water,  dried  over  anhydrous  sodium 
sulfate,  filtered,  and  distilled.  It  boiled  between  68-7U0  at 
20  mm. , and  the  yield  was  105-115  g.  or  57-62 % of  the  theory. 

( 20 ) 

3.  Preparation  of  acrylic  nitrile. 

An  intimate  mixture  of  90  g.  of  phosphorus  pent  oxide 
and  100  g.  of  sand  was  poured  into  a dry  liter  Claisen  flask.  Over 
the  side  arm  of  the  flask  was  placed  an  ordinary  distilling  flask 
as  a receiver,  and  a thermometer  was  placed  in  position.  There 
were  dropped  upon  the  phosphorus  pentoxide  sand  mixture  25  g.  of 
ethylene  cyanhydrin  in  three  portions,  the  flask  being  vigorously 
shaken  after  each  addition,  to  thoroughly  mix  the  contents.  If  a 
thorough  mixing  were  not  obtained,  a large  portion  of  the  phos- 
phorus pentoxide  would  have  remained  unreacted  upon  in  the  bottom 
of  the  flask.  The  mixture  was  then  heated  either  with  a free  flame 
or  an  oil  bath  at  250°,  the  receiver  being  well  cooled.  About  5 g. 
of  nitrile  distilled  over  between  60-80°.  This  was  removed,  and 
the  receiver  replaced.  There  was  then  applied  a low  vacuum,  which 
was  built  up  gradually  so  that  the  nitrile  which  distilled  did  not 
pass  through  the  receiver  uncondensed.  Two  or  three  more  grams  of 
nitrile  were  thus  obtained.  The  nitrile  was  distilled  once  before 
use,  and  boiled  between  74-78° t at  atmospheric  pressure,  most  of 
it  coming  over  at  78°.  The  yield  was  7 g.  or  37 c/o  of  the  theory. 


* 


* 


, 


18. 


21 


4.  Preparation  of  'V-chlorbutyronitrile . 

In  a 5 1.  round  bottom  flask  were  placed  920  g.  of 
trimethylene  chlorbromide  and  2 1.  of  95  > alcohol.  The  f la  sir  was 
fitted  to  an  efficient  reflux  condenser,  and  its  contents  heated 
to  boiling.  There  was  then  dropped  into  the  mixture  285  g.  of 
sodium  cyanide  dissolved  in  400  cc.  of  water,  the  addition  requir- 
ing about  1 hour.  The  reaction  started  almost  immediately,  as  was 
shown  by  a darkening  of  the  solution,  and  the  separation  of  a pre- 
cipitate of  sodium  bromide.  The  solution  was  refluxed  for  11/2 
hours,  and  the  alcohol  then  distilled  off  directly.  When  the  resi- 
due became  thick  and  no  more  alcohol  distilled  at  the  heat  of  the 
steam  cone,  the  distillation  was  discontinued.  The  alcoholic  dis- 
tillate contained  practically  all  of  the  unchanged  trimethylene 
chlorbromide,  which  could  be  recovered  by  diluting  with  water  and 
separating  the  layer  of  chlorbromide.  In  this  manner  5u-70  g.  of 
unchanged  material  were  recovered. 

About  11/21.  of  water  were  then  added  to  the  residue 
in  the  flask,  and  the  layer  of  nitrile  separated.  This  was  dried 
over  anhydrious  sodium  sulfate  and  filtered.  The  water  was  extracte 
twice  with  benzene,  one  liter  being  used  for  each  extraction.  The 
benzene  was  dried  over  anhydrous  sodium  sulfate,  filtered,  and 
distilled.  The  nitrile  which  remained  behind  was  combined  with 
the  dried  fraction  above,  and  distilled.  Fraction  98-102°,  146  g. 
Fraction  102-108°,  51  g.  at  55  mm.  pressure.  The  product  was 
redistilled,  and  the  fraction  from  89°  to  91°  at  15  mm.  collected. 
The  yield  was  170  g. , which  is  17.7%  of  the  theory. 

There  was  obtained  in  the  higher  boiling  fraction  70  g. 
of  trimethylene  cyanide. 


1 . 


19. 

B.  CONDENSATIONS  OP  NITRILES  WITH  RESORCINOL. 

1.  An  attempt  to  condense  ethylene  cyanhydrin  with 
resorcinol . 

Seventy  one  grams  of  ethylene  cyanhydrin  and  110  g.  of 
resorcinol  were  dissolved  in  400  cc.  of  dry  ether,  and  30  g.  of 
powdered  zinc  chloride  were  added.  Dry  hydrogen  chloride  was  then 
passed  in  until  the  ether  was  saturated.  The  solution  became  red 
immediately,  the  depth  of  color  increasing  steadily  as  the  solutior 
became  more  and  more  saturated.  At  the  end  of  about  fifteen  minutes 
a turbidity  became  apparent,  and  shortly  afterwards  a liquid  layer 
separated.  The  flask  was  allowed  to  stand  for  one  day,  and  then 
more  hydrogen  chloride  was  passed  in.  After  another  day,  the  depos 
-it  had  become  viscous,  red,  and  gummy.  The  ether  was  decanted, 
and  the  gum  washed  with  25U  cc.  of  fresh  dry  ether.  It  was  then 
treated  with  300  cc.  of  water,  and  warmed  on  a steam  bath  for  one 
hour.  A clear  solution  resulted. 

The  water  solution  was  made  alkaline  to  sodium  carbonate  , 
and  extracted  three  times  with  ether,  two  liters  being  used.  The 
ether  was  dried  over  sodium  sulfate,  filtered,  and  distilled. 

There  remained  42  g.  of  a brown  oil. 

In  order  to  identify  this  oil,  a portion  was  boiled  in 
an  alkaline  solution  with  benzoyl  chloride  in  excess.  A white  oil 
separated  from  the  alkaline  solution,  which  oil  solidified  on 
cooling.  It  was  filtered  off,  washed  thoroughly  with  alkali,  and 
then  with  water.  It  crystallized  out  of  95/o  alcohol  in  colorless 
plates,  and  melted  at  107-114°.  When  mixed  with  resorcinol  dibenz- 
oate (m.p.  117°)  it  melted  from  112.5-117.5°.  Therefore  no  conden- 
sation had  occurred. 


. 


. 

. 


. 


20. 

The  alkaline  water  solution  was  acidified,  and  the  water 
evaporated  under  vacuum.  When  it  had  become  concentrated,  the  sol 
-ution  was  allowed  to  stand,  when  four  grams  of  hard  nuclear  crys- 
tals of  2-4-dihydroxy  ^-phenylpropionic  acid  separated. 

To  determine  whether  or  not  the  zinc  chloride  had  had 
a dehydrating  action  upon  the  ethylene  cyanhydrin  and  prevented  the 
condensation,  the  above  was  repeated,  the  zinc  chloride  being 
omitted.  Practically  identical  results  were  obtained. 

The  condensations  of  ethjhLene  cyanhydrin  with  resorcinol 
mono-and  di-methyl  ethers  were  also  tried,  but  in  no  case  could  a 
condensation  product  be  isolated. 

2.  An  attempt  to  condense  ^-cyanethyl-acetate  with 

re so  rcinol. 

In  a 500  cc.  flask  were  dissolved  together  47  g.  of 
P-cyanethyl-acetate , 45  g»  of  resorcinol,  25u  cc.  of  dry  ether, 
and  15  g»  of  powdered  zinc  chloride.  Dry  hydrogen  chloride  was 
then  passed  into  the  mixture  until  it  was  saturated.  At  the  end 
of  1/2  hour,  a turbidity  resulted,  which  was  soon  followed  by  the 
separation  of  a viscous  liquid  on  the  bottom  of  the  flask.  After 
twelve  hours  standing,  more  hydrogen  chloride  was  passed  in,  and 
the  flask  sealed  for  several  more  hours.  The  ether  was  decanted, 
and  the  residue  treated  with  100  cc*  of  water.  The  product  dissolved 
completely.  The  flask  was  heated  for  2 hours  on  a steam  bath, 
and  cooled,  but  no  product  separated.  The  solution  was  extracted 
twice  with  250  cc.  portions  of  ether,  the  ether  dried  over  anhy- 
drous sodium  sulfate,  filtered,  and  distilled.  A small  amount  of 
oil  remained,  but  it  could  not  be  purified. 


♦ 


. 


'4 


■ 


. 


21. 

The  ether  layer  from  the  reaction  mixture  was  evaporated 
and  the  residue  distilled  under  vacuum.  There  were  recovered  36  g. 
of  resorcinol,  melting  at  95-106°.  i^ixed  with  resorcinol  it  melted 
from  103-109°.  The  reaction  mixture  was  therefore  discarded. 

3.  Condensation  of  ^-chlorpropionitrile  with  resorcinol. 

In  a 2 1.  flask  was  placed  130  g.  of  pure  resorcinol, 

90  g.  of  ^-chlorpropionitrile , and  7oO  cc.  of  dry  ether,  forty 
grams  of  zinc  chloride  were  fused,  powdered,  and  added  to  the  ether 
solution.  Dry  hydrogen  chloride  was  then  passed  into  the  ether  as 
long  as  it  was  absorbed,  and  then  the  flask  was  sealed  and  allowed 
to  stand  overnight.  Dry  hydrogen  chloride  was  again  slowly  passed 
in  for  a period  of  five  hours,  and  the  flask  allowed  to  stand  36 
hours  longer.  The  mass  of  crystals  which  separated  were  then  fil- 
tered with  suction,  and  washed  with  dry  ether.  The  ether  was 
allowed  to  stand  and  after  2 more  days,  38  g.  more  of  solid  had 
formed,  un  standing  a week  more,  25  additional  grams  of  crystals 
were  obtained. 

The  solid  was  dissolved  in  45u  cc.  of  water,  and  heated 
on  a steam  bath  for  four  hours.  An  oil  layer  first  separated,  and 
then  went  into  solution  as  the  heating  was  continued.  The  solution 
was  then  cooled,  and  allowed  to  stand  overnight,  when  6t>.5  g*  of 
2-4-dihyaroxy  $-phenylpropionic  acid  were  filtered  off.  The  aqueous 
filtrate  was  evaporated  under  vacuum  to  about  175  cc.  and  allowed 
to  stand,  when  a second  crop  of  crystals,  weighing  22.5  g.  was 
obtained,  un  further  concentration  of  the  filtrate,  only  inorganic 
salts  separated  out.  Total  yield,  lu9  g.  or  56 u/o  of  the  theory. 


• • 


. 


22. 


Analysis:  Subst.  .3679  g.  GO^  .7962  g. 

Cal.  CgH1004  C 59.34% 

jj’ound  C 59.05 % 


H.,0  . 1799  g. 

H 5.49% 

H 5.49% 


2-4-dioxy  A-phenylpropionic  acid,  as  it  was  obtained, 
was  light  brown,  and  did  not  lose  its  color  even  when  boiled  with 
bone  black.  When  prepared  from  its  pure  lactone,  it  may  be  obtained, 
perfectly  colorless.  The  crystals  are  hard,  shiny  nodules,  and 
melt  at  165°  with  decomposition.  The  acid  crystallizes  out  of  water 
slowly,  is  insoluble  in  benzene,  toluene,  chloroform,  and  ligroin, 
difficulty  soluble  in  ether,  very  soluble  in  methyl,  ethyl,  iso- 
propyl, and  butyl  alcohols,  acetone,  and  ethyl  acetate.  It  decom- 
poses sodium  carbonate  very  readily  in  the  cold. 

A portion  of  the  solid,  when  lb  1 ted  in  a 2”  test  tube, 
showed  no  signs  of  decompositon  until  the  melting  point  was 
reached,  when  bubbles  permeated  the  clear  light  brown  liquid,  and 
moisture  collected  in  the  upper  portions  of  the  tube.  The  liquid 
recrystallized  on  standing,  and  then  malted  at  124-126°. 

It  was  found,  however,  that  hydroumbellic  acid,  as  this 
acid  is  called,  when  heated  above  125°  for  a period  of  2 hours, 
melted  down  to  a dark  red  mass,  which  lost  24%  by  weight  instead 
of  the  9.39%,  which  is  the  theoretical  loss  in  weight  upon  the 
formation  of  the  lactone. 

Neutral  equivalent  of  2-4-dihydroxy  /3-phenyl propionic 


acid . 

Subst.  .2973  g.  NaOH  (.07}7  N.  ) 24.94  cc. 

Neutral  equivalent  calculated  182,  found  171. 
2-4-d ioxy /3_phenyl  propionic  acid  was  prepared  by 
Hlasiwetz  by  the  reduction  of  umbelliferonL^iut  the  constants 


, 


. 


23. 

given  by  him  are  found  to  differ  from  the  constants  of  a pure  sampL:  . 
Hlasiweta  states  that  the  acid  decomposes  when  heated  above  110°, 
whereas  a pure  sample  melts  at  165°  if  not  heated  too  slowly.  Upon 
very  slow  heating,  enough  of  the  lactone  is  formed  to  cause  a 
lowering  of  the  melting  point.  Hlasiwetz  isolated  a compound  which 
analyzed  for  the  lactone  of  hydroumbellic  acid,  but  as  he  was  unabL: 
to  purify  it,  did  not  identify  it,  nor  give  constants  for  it. 

Isolation  of  the  intermediate  imide-hydrochloride . 

Five  grams  of  resorcinol  and  5 g.  of  ^-chlorpropionitril : 
were  dissolved  in  50  cc.  of  dry  ether,  and  hydrogeh  chloride  was 
passed  in  until  the  ether  was  saturated.  The  f 1b sic  was  then  sealed 
and  allowed  to  stand.  After  12  hours  a small  amount  of  precipitate 
had  formed,  but  the  flask  was  allowed  to  stand  for  a week  before 
the  ether  was  filtered.  There  were  thus  isolated  2.5  g.  of  colories: 
solid.  The  crude  product  decomposed  from  178-180°.  On  being  dried, 
it  becamesticlcy,  and  it  was  washed  with  absolute  alcohol  saturated 
with  hydrogen  chloride,  and  then  with  acetone.  The  product  was  then 
dried  in  air  until  the  odor  of  acetone  and  of  hydrochloric  acid 
was  gone. 

Analysis:  Chlorine,  by  peroxide  fusion  method. 

1.  Subst.  .2778  g.  AgKOg  (.1050  N.  ) 17.72  cc. 

Cal.  C9H1002NC1  Cl  18%.  Found  Cl  23.72%. 

2.  Subst.  .5020  g.  AgKOg  32.55  cc. 

Found  01  24.11% 

A portion  of  this  compound,  when  treated  with  water, 
was  instantly  converted  into  an  oil,  which  solidified  on  cooling. 


. 


£4. 


This  new  compound  crystallized  readily  from  toluene,  and  was  shown 
to  be  7-hydroxy  chromanone , or  the  lactone  of  £-4-dihydroxy  P- 
phenylpropionic  acid. 


Preparation  of  7-hydroxy  chromanone -£ . 

Two  grams  of  2 -4 -&i hydroxy  ^-phenyl  propionic  acid  were 


heated  in 

an  oven  at  130-135° 

for 

two  hours. 

The  melt  was  allowed 

to  cool, 

and  then  was  crystallized 

from  toluene.  A white  solid 

resulted , 

melting  at  130-132°. 

On 

recrystall 

ization,  it  melted  at 

132-133°. 

Analysi s : 

Subst.  .1560  g. 

o 

o 

.3795  g. 

H20  .0072  g. 

Calculated  CgHgO^ 

C 

65.85% 

H 4 . 88% 

Pound 

c 

66.33 % 

H 4.96% 

7-hydroxy  chromanone -£  separated  from  solution  in  color- 
less cubical  crystals.  It  was  very  soluble  in  methyl,  ethyl,  and 
butyl  alcbhols,  acetone,  and  acetic  acid;  insoluble  in  benzene, 
water,  ligroin,  chloroform,  and  carbon  tetrachloride.  It  was 
insoluble  in  sodium  carbonate  until  the  solution  was  heated,  when 
it  went  into  solution,  and  did  not  come  out  again  until  the  solu- 
tion was  acidified  and  allowed  to  stand  for  some  time.  It  then 
deposited  in  the  form  of  hard  crystals  of  2-4-dihydroxy  ^-phenyl 
propionic  acid.  It  gave  no  coloration  with  ferric  chloride  on 
warming,  but  when  the  solution  was  allowed  to  stand  for  some  time, 
a brown  coloration  developed. 

This  lactone  did  not  react  with  butyl  nitrite  to  give  a 
nitroso  derivative  under  the  same  conditions  as  2-4-dihydroxy 
^-phenyl propionic  acid. 


. 


25. 

Preparation  of  the  acetate  of  7-hydroxy-chromanone-2. 
Seven  grams  of  2-4-dihydroxy  £-phenylpropionic  acid 
were  dissolved  in  10  g.  of  acetic  anhydride  (2  mols. ) and  heated 
on  a water  hath  for  one  hour.  The  solution  developed  a light  red 


color.  The  mixture  was  cooled. 

and  poured 

into  70 

cc.  of 

cold  wate 

whereupon  a yellow  crystalline 

substance 

was  thrown  out . 

It  melted 

at  100.5-108°  when  unpurified. 

The  yield 

was  9 g. , 

wjiich 

was  prac- 

tically  quantitative.  It  was  recrystallized  twice 

0 

alcohol,  after  which  it  melted  at  111-112  . 

from  20%  methyl 

Analysis:  Subst.  .3116  g. 

U02 

.7382  g. 

H2° 

.1357  g. 

Cal.  ciih1D04* 

c 

64.1% 

H 

4.67% 

Found 

c 

64.63 

H 

4.83 

The  acetate  was  in  the  form  of  colorless  needles, 
insoluble  in  sodium  carbonate  until  heated,  v/hen  it  decomposed.  It 
hydrolyzed  readily  when  boiled  with  water,  giving  2-4-dihydroxy 
^-phenylpropionic  acid. 

Preparation  of  2-4-dimethoxy  ^-phenylpropionie  acid. 

In  100  cc.  of  10%  sodium  hydroxide  were  dissolved  35  g. 
of  2-4-dihydroxy  P-phenylpropionic  acid,  and  36  g.  of  dimethyl 
sulfate  were  added.  The  solution  was  thoroughly  shaken,  and  then 
warmed  on  a steam  bath  under  a reflux  condenser.  A reaction  took 
place,  in  which  heat  was  evolved,  and  the  dimethyl  sulfate  passed 
into  solution.  There  were  then  added  another  100  cc.  of  10%  sodium 
hydroxide  and  35  g.  of  dimethyl  sulfate,  and  the  mixture  again 
heated  until  all  of  the  dimethyl  sulfate  was  decomposed.  The  sol- 
ution was  then  cooled,  acidified,  and  stirred,  when  needle  crystals 
separated.  After  standing  for  about  an  hour,  the  solution  was 


26. 

filtered,  and  the  precipitate  dried.  The  compound  melted  at  98-103° 
and  the  yield  was  28.5  g.  or  68%  of  the  theory. 

A portion  of  the  compound  was  recrystallized  from  water, 
in  which  it  was  difficulty  soluble,  and  it  then  melted  at  102-103°. 
On  a second  recrystallization,  it  melted  at  102.5-103.5°. 


Analysis : - 

Subst.  .1260  g. 

co2 

.6896  g. 

h2o 

.1739 

Cal-  C11H14°4- 

c 

62.8% 

H 

6.6% 

Found 

c 

62.87% 

H 6 

6.5  % 

This  was  therefore  beyond  doubt  the  acid  prepared  by 

(23)  ch30  r^lOCH 

W.Will  , by  the  reduction  of  dimethoxy  umbellic  acid 
CH.COOH.  The  melting  point  given  by  him  was  105°. 

Neutralization  equivalent 

Subst.  .1260  g.  NaOH  (.0717  N. ) 8.74  cc. 

Cal.  N.E.  210  Found  201. 

Preparation  of  6-nitroso-7-hydroxy  chromanone-2. 

In  50  cc.  of  95%  alcohol  were  dissolved  3 g.  of  2-4- 
dihydroxy  JB>-phenylpropionic  acid,  and  to  the  solution  were  added 
4 g.  of  butyl  nitrite,  which  had  been  freshly  distilled,  and  boilec 
at  78°.  The  flash  was  then  cooled  under  running  water,  and  10  cc. 
of  concentrated  hydrochloric  acid  added.  Fumes  of  nitric  oxide 
were  evolved,  heat  was  generated,  and  a red  precipitate  formed. 

40  cc.  more  of  concentrated  hydrochloric  acid  were  then  added,  and 
the  flask  allowed  to  stand  for  twenty  to  thirty  minutes.  The  solid 
was  then  filtered  off,  washed  twice  with  cold  water,  and  dried. 

The  yield  was  4 grams,  or  practically  quantitative.  The  washed 
compound  was  of  a light  cream  color,  but  on  exposure  to  air,  it 


. 


. 


- 


. 


27. 

turned  green.  In  other  preparations,  the  solid  came  out  as  a red 
precipitate  from  which  the  color  was  difficult  to  remove,  even 
when  "boiled  with  bone-black. 

.Four  grams  were  dissolved  in  70  cc.  of  boiling  water, 
and  filtered  hot.  The  aqueous  solution  turned  very  green,  but  the 
product  separated  out  cream  colored.  It  was  filtered  off,  and 
placed  in  a dessicator  over  sulfuric  acid,  in  which  it  did  not 
discolor  on  standing.  The  weight  of  the  dried  product  was  2.5  g. 
and  it  melted  at  147.5-148°. 

Analysis:  Nitrogen  by  Dumas  method. 

o 

Subst.  .1873  g.  H collected  13.1  cc-  at  26  and 

737.3  mm. 

Cal.  C9H704  N 7.25  % i?ound  7.61c/o 

6-nitroso  7-hydroxy  chromanone -2  is  an  amorphous  powder 
which  slowly  turned  dark  brown  at  110°.  It  was  difficulty  soluble 
in  cold  alcohol,  but  readily  soluble  hot.  When  once  dissolved,  it 
did  not  come  out  again  on  cooling.  It  was  practically  insoluble  in 
cold  water,  and  decomposed  sodium  carbonate,  acting  as  a monobasic 
acid,  although  due  to  coloration  of  the  solution  when  alkali  was 
added,  no  quantitative  titration  could  be  obtained. 

To  prove  that  the  nitres©  group  was  in  the  benzene 
portion  of  the  molecule  and  not  in  the  pyrone  ring,  an  attempt 
was  made  to  hydrolyze  it. 

Twenty  grams  of  6-nitroso  7-hydroxy  chroinanone-2  were 
treated  with  80  cc*  of  water  and  20  g.  of  concentrated  sulphuric 
acid.  The  flask  was  connected  to  an  air  condenser,  and  a tube 
connected  from  the  top  of  the  condenser  to  a flask  containing  a 
solution  of  barium  hydroxide.  The  flask  was  then  heated  on  a steam 


. 


• • 


* 


. 


. 


■ 


. ! 


28. 


bath.  Almost  immediately  a gas  was  evolved,  and  a precipitate  forme 
in  the  barium  hydroxide.  This  precipitate  was  readily  soluble  in 
acids  with  effervescence,  carbon  dioxide  oeing  evolved. 

After  four  hours  of  heating,  the  reaction  mixture  was 
cooled,  and  extracted  four  times  with  ether,  1 1/2  1.  being  used. 
There  were  about  2 g.  of  carbon  left  in  suspension  intthe  water. 

The  ether  was  dried  over  anhydrous  sodium  sulfate,  filtered,  and 
distilled.  A brown,  viscous  liquid  remained.  It  decomposed  sodium 
carbonate  readily  in  the  cold,  and  reacted  acid  to  litmus,  which 
showed  it  to  be  an  organic  acid.  It  was  placed  in  a dessicator, 
and  allowed  to  stand  for  nearly  a month,  but  failed  to  crystallize. 
Numerous  attempts  were  made  to  prepare  a derivative  of  this  acid, 
but  all  were  unsuccessful. 

After  the  ether  extraction,  the  sulfuric  acid  solution 
was  made  alkaline  with  excess  of  sodium  hydroxide  and  boiled  with 
15  g.  of  benzoyl  chloride.  On  cooling  the  solution,  a solid  sep- 
arated from  the  alkaline  reaction  mixture.  This  was  filtered  off, 
washed  with  dilute  alkali,  and  then  with  water.  The  solid  was  in 
the  form  of  cream  colored  needles,  6 g.  being  obtained.  It  crys- 
tallized out  of  water,  and  melted  at  124.5-125.5°.  Mixed  with 
benzamide,  it  melted  at  124.5-126.5°. 

The  formation  of  carbon  dioxide  and  ammonia  upon  the 
hydrolysis  of  the  nitroso  compound,  and  the  formation  of  a liquid 
acid  which  could  not  be  purified  point  to  a deep  seated  change  in 
the  molecule.  No  trace  of  aldehyde  could  be  detected  either  in  the 
gas  evolved,  in  the  acid  extracted  by  the  ether,  or  in  the  sul- 
phuric acid  residue.  Were  the  nitroso  group  in  the  aliphatic  por- 
tion of  the  molecule,  there  seems  little  doubt  but  that  2-4-^ 


(L 


. 


. 


. 


. 


29. 


dihydroxyphenyl  acetaldehyde  could  have  been  isolated,  or  at  least 
detected.  It  was  therefore  concluded  that  the  nitroso  group  was  in 
the  benzene  ring. 


Preparation  of  umbel life rone . 


( 24  ) 


i 


In  a 500  cc.  round  bottom  flash  were  placed  26  g.  of  malic 
acid  and  23  g.  of  resorcinol.  Over  the  mixture  were  then  poured 
100  g.  of  concentrated  sulphuric  acid,  and  the  flask  was  stirred 
until  complete  solution  had  resulted.  The  flask  was  connected  to 
a reflux  condenser,  and  heat  was  applied  with  a free  flame.  When 
formic  acid  began  to  be  evolved,  the  flame  was  removed,  and  the 
flask  was  shaken  vigorously.  In  a short  time  the  reaction  mixture 
solidified  to  a cream  colored  product.  After  this  first  reaction 
had  ceased,  the  flask  was  heated  gently,  with  occasional  stirring, j 
for  a period  of  three  hours,  during  which  time  the  solid  gradually 
dissolved.  The  entire  mixture  was  then  poured  into  2 1.  of  ice  and  ; 
water,  and  allowed  to  stand  for  five  or  six  hours.  A red  precipi- 
tate of  umbelliferone  separated.  The  solution  was  filtered,  and  the 
precipitate  washed  thoroughly  with  water,  and  dried.  The  yield  was 
9 g. 


A portion  of  the  product  was  recrystallized  from  water,  bone-f 
black  being  added  to  remove  some  of  the  color.  Orange  crystals 
melting  at  222.5-225°  were  obtained.  The  melting  point  of  umbellif-r 
erone  is  223-224°. 


Eeduction  of  umbelliferone. 

(Preparation  of  2-4-dihydroxy  /3-phenylpropionic  acid) 

2.4  g.  of  umbelliferone  were  dissolved  in  12  cc.  of 


' 


4 


■ 


. 


30. 


10%  sodium  hydroxide,  a red  coloration  resulting.  To  prevent  the 
solution  from  becoming  too  concentrated,  10  cc.  of  water  were  then 
added.  Sodium  amalgam  was  dropped  into  the  flask  in  small  amounts 
until  the  red  color  had  disappeared,  about  1 hour  being  required. 
The  solution  was  acidified  with  hydrochloric  acid,  filtered,  and 
allowed  to  stand.  Ked  crystals  deposited.  They  decomposed  at  149- 
157°,  and  when  mixed  with  2-4-dihydroxy  £>-phenylprop  ionic  acid, 
melted  with  decompositi cn  at  155-159°.  The  yield  was  .6  gram. 

Preparation  of  acetate  of  7-hydroxy  chromanone-2. 

Into  5 cc.  of  acetic  anhydride  were  placed  .5  g.  of  the 
2-4-dihydroxy  7^-phenylpropionic  acid  from  umbellife rone , and  the 
solution  was  heated  for  20  minutes.  The  contents  of  the  flask  were 
then  poured  into  20  cc.  of  water,  and  stirred  until  the  excess  of 
acetic  anhydride  was  decomposed.  A brown  solid  remained.  This  was 
filtered,  washed  thoroughly  with  water,  and  crystallized  from  30 
cc.  of  20%  methyl  alcohol.  It  came  out  as  a white  powder,  melting 
at  lu9-112°.  Mixed  with  the  acetate  prepared  from  resorcinol  and 
/p-chlor  pr  opioni  tri  le,  it  melted  at  112-112.5  . The  products  were 
therefore  identical. 

4.  Condensation  of  acrylic  nitrile  with  resorcinol. 

Twelve  grams  of  resorcinol  and  6 g.  of  acrylic  nitrile 
were  dissolved  in  70  cc.  of  dry  ether,  and  4 g.  of  powdered  zinc 
chloride  added.  Dry  hydrogen  chloride  was  then  passed  in  until  the 
ether  was  saturated,  and  the  flask  was  allowed  to  stand  for  twelve 
hours.  At  the  end  of  that  time,  a heavy  white  crystalline  product 
had  separated.  The  ether  was  decanted,  and  a small  portion  of  the 


1 


31. 

solid  was  removed  and  treated  with  water.  It  immediately  became  an 
oil,  and  when  it  was  cooled, isolidified . It  crystallized  from 
toluene,  and  melted  at  132.5.134°.  Mixed  with  7-hydroxy  chromanone 
-2,  it  melted  at  133-134°. 

The  remainder  of  the  solid  was  boiled  with  50  cc.  of 
water  for  1/2  hour,  and  then  allowed  to  stand.  Crystals  separated, 
which  melted  with  decomposition  at  152-158°.  The  mixed  melting 
point  math  2-4-dihydroxy  jB-phenylpropionic  acid  was  155-158°. 

The  yield  was  4 g.  or  20$  of  the  theory. 

5.  Condensation  of  y-chlorbutyronitrile  with  resorcinol. 

Sixty  four  grams  of  resorcinol  and  60  g.  of  'y-chlorbutyr 
-nitrile  were  dissolved  in  400  cc*  of  drj?-  ether,  and  30  g.  of  pow- 
dered zinc  chloride  added.  Dry  hydrogen  chloride  was  then  passed 
in  in  a rapid  stream  for  two  hours.  The  solution  turned  red,  and  a 
small  amount  of  liquid  separated.  Por  two  successive  days,  for  an 
hour  each  day,  hydrogen  chloride  was  passed  in,  the  amount  of 
liquid  deposited  increasing  slowly  during  this  time.  After  six  days 
the  liquid  layer  which  had  fomed  had  entirely  crystallized. 

The  ether  was  filtered,  and  the  residue  takenup  in  250 
cc'.  of  water.  It  was  heated  for  three  hours  on  the  steam  bath.  An 
oil  layer  separated  at  first,  and  went  into  solution  as  heating  was; 
continued.  On  standing,  crystals  formed.  They  were  filtered,  and 
dried.  Yield,  24.5  g.  or  20.8$  of  the  theory. 

Ten  grams  of  the  product  were  dissolved  in  57  cc.  of 
boiling  water,  and  filtered  hot.  An  oil  separated,  which  on  being 
cooled  and  stirred,  solidified.  The  weight  recovered  was  9.5  g. , 


. 


, 


32. 

o 

and  a portion  melted  at  89-99  . 

2-4-dihydroxy  y-phenylbutyric  acid  is  a colorless,  crys- 
talline solid,  which  came  out  of  water  in  plates  with  one  molecule 
of  water  of  crystallization,  which  it  lost  at  about  90°.  After 

several  recrystallizations  from  water,  one  sample  melted  from  89° 
o 

to  104.5  . On  standing,  the  melt  resolidified,  and  remelted  at  118- 

119°. 

Moisture  determination:  Subst.  . 7322  g.  Heated  at  80°  for  11/2 

o 

hours,  and  then  at  95  for  1 hour.  H^O  lost  .0655  g.  Cal.- 

H 0 .0615  g. 

2 

o 

Subst.  .5297  g.  Heated  1 hour  at  80-85  , and  1 hour 

at  100°.  HO  lost  .0471  g.  or  8.89%.  Cal.  loss  8.4% 

& 

The  anhydrous  product  was  readily  crystallized  from 
benzene,  and  melted  at  118.5-119°.  It  was  in  the  form  of  colorless 
plates. 


Analysis:  Subst.  .2560  g. 

Gal*  C10H12U4 
Found 

Neutralization  equivalent. 

Subst.  .1491  g. 
Cal.  N.E.  198 


CO 

4 

c 

c 


.3640  g. 
61.22% 
60.96% 


H 0 
2 

H 

H 


.0865  g. 
6.12% 
5.95% 


NaOH  ( .0717  N. ) 
Found  208. 


9.98  cc. 


A portion  of  the  anhydrous  2-4-dihydroxy  y-phenylbuty rio 

o . 

acdd  was  heated  in  an  oven  at  123-134  for  1/2  hour.  The  solid 
melted  down  to  a red  liquid.  It  solidified  on  cooling,  and  crys- 
tallized from  dry  toluene  as  a yellow  powder,  melting  113-117°. 
Mixed  with  2-4-dihydroxy  y -phenyl  butyric  acid,  it  melted  at  115- 
118°.  Therefore  no  lactone  was  formed. 


* 


33. 


In  order  to  study  the  int erme  diat e products  formed  in  the 
condensation  of  resorcinol  arrt  y-chlorbutyronitrile , another  con- 
densation was  run  under  the  same  conditions  as  are  given  above. 

The  product  obtained  was  treated  with  water,  warmed  to  50°,  and 
then  cooled.  The  oil  which  formed  solidified,  and  the  solid  melted 
at  £14-216°.  When  it  was  washed  with  water,  the  melting  point 
dropped  to  190-192°,  and  the  compound  became  yellow.  This  could  be 
crystallized  from  methyl  alcohol,  and  when  the  product  obtained 
was  washed  with  methyl  alcohol  saturated  with  hydrogen  chloride, 
the  melting  point  went  up  to  215-216°,  and  the  solid  became  white.  , 
Analysis:  Subst..3859  g.  AgNO^  (.1050  14.)  25.77  cc . 

Cal.  C10H1302NC1£  Cl  28.4°  Found  Cl  25.04% 

Sub st . .4489  g.  AgNOg  30.42  cc. 

(Parr  bomb  fusion)  Found  Cl  25.22%. 

This  product  was  washed  thoroughly  with  dilute  sodium 
bicarbonate,  and  then  with  water.  The  yellow  compound  obtained 
was  then  analyzed  for  halogen.  It  melted  at  193.5-194.5°. 

Analysis:  Subst.  .2623  g.  AgNOg  (.1050  N.  ) 14.04  cc. 

Cal.  cl0Hi2°2NC1  01  16 -5%  Found  Cl  18.6% 

Subst.  .3382  g.  AgUO^  17.86  cc. 

Found  Cl  19.6% 

The  wash  waters,  on  acidification,  gave  a small  amount 
of  white  solid,  which  proved  to  be  2 -4 -d ihydr oxy  y-phenylbutyric 

acid . 

C.  CONDENSATIONS  OF  NITRILES  WITH  RESORCINOL  MONOMETHYL  ETHEI . 

1.  Condensation  of  /3-chlorpropionitrile  with  resorcinol 
monomethyl  ether. 


34. 

Thirty  grains  of  resorcinol  monomethyl  ether  and  22  g.  of 
P -chlorpropionitrile  were  dissolved  in  300  cc.  of  dry  ether,  and 
20  g.  of  powdered  zinc  chloride  added.  The  ether  was  cooled  in  an 
ice  bath,  and  dry  hydrogen  chloride  passed  in  until  it  was  saturate* 
The  flask  was  then  allowed  to  stand  overnight.  A viscous  syrupy 
mass  had  formed  in  the  bottom  of  the  flask.  The  ether  was  decanted, 
and  the  residue  treated  with  30  cc.  of  water.  After  standing  over- 
night, a small  amount  of  solid,  and  some  liquid  had  separated.  The 
solid  was  removed  from  the  oil  by  filtration  with  suction,  and  when 
dried,  weighed  3.5  g.  The  liquid,  which  weighed  about  10  g.  was 
not  worked  up  at  this  time. 

The  ether  solution  was  evaporated  under  vacuum,  and  the 
unchanged  ^-chlorpropionitrile  distilled,  12  g.  being  recovered. 
Then  there  distilled  a higher  boiling  fraction  which  proved  to  be 
unchanged  resorcinol  monomethyl  ether,  of  which  21  g.  were  recov- 
ered. The  residue  in  the  flask  aid  not  distil,  but  solidified  on 
cooling.  It  weighed  6 gram3.  A small  portion  was  crystallized  from 
dilute  alcohol,  when  it  melted  from  118-122°.  After  two  recrystal- 
lizations, it  melted  at  126-127.5°.  It  proved  to  be  2-hydroxy  4- 
rae thoxy  ^-phenylpropionit rile . It  was  insoluble  in  sodium  carbonate 
but  soluble  in  sodium  hydroxide,  being  thrown  out  again  unchanged 
on  acidification.  When  boiled  with  alkali, it  evolved  ammonia,  and 
gave  on  acidification,  colorless  crystals  of  2-hydroxy  4 -met ho xy 
P- phenyl  propionic  acid. 

Analysis:  Nitrogen  by  Jurnas  method. 

Subst.  .3718  g.  N collected  27.2.CC.  at  28°,  749  mm. 

Calculated  H 7.9  °/o 

Found  H 8.0% 


35. 

The  solid  obtained  by  filtration  proved  to  be  2-hydroxy 
4-methoxy  A-phenylpropionic  acid.  It  was  recrystallized  from  water f 
in  which  it  was  difficulty  soluble,  4.5  g.  dissolving  in  200  cc. 

It  came  out  as  white  kernels,  melting  at  138-139°. 

Analysis:  Subst.  .3819  g.  COg  .8604  g.  H^O  .1982  g. 

Cal.  C10H1204  C 61.2%  H 6.1% 

tfound  C 61.4%  H 5.8% 

The  acid  was  readily  soluble  in  sodium  bicarbonate,  and 
was  thrown  out  again  by  acids  unchanged.  It  was  very  soluble  in 
alcohol,  acetone,  and  acetic  acid.  It  was  insoluble  in  cold  benzene 
and  toluene. 

A gram  sample  of  2-hydroxy  4-methoxy  ^-phenylpropionic 
acid  was  heated  in  an  oven  at  132°.  The  solid  melted  down,  and  was 
removed  at  the  end  of  3/4  hours.  There  was  no  trace  of  discoloratiojji 
and  a thick  syrup  remained.  This  did  not  crystallize  on  standing, 
nor  would  it  crystallize  out  of  any  solvents  tried.  The  product 
proved  to  be  insoluble  in  cold  sodium  hydroxide,  but  dissolved  on 
warming,  and  on  acidification,  yielded  the  original  acid. 

About  twenty  grams  of  the  7-methoxy  chromanone-2  were 
placed  in  a 50  cc.  Cl&isen  flask,  and  distillation  at  6 mm*  pres- 
sure was  attempted.  A small  portion  of  colorless  oil  came  over 
from  170-210°,  but  the  remainder  of  the  product  carbonized  in  the 
flask.  As  the  chemical  behaviour  of  the  liquid  left  no  doubt  as 
to  the  lactone  nature  of  the  compound,  no  further  attempt  to 
purify  it  has  been  made  up  to  this  time. 


' 


36 . 

D.  CONDENSATION  OP  NITRILES  WITH  ORCINOL. 

1.  Condensation  of  orcinol  wi  th  /3-chlorpropionitri  le  . 

Pive  grams  of  orcinol  were  dissolved  with  5 g.  of  ^-chlor 
propionitrile  in  100  cc.  of  dry  ether,  and  5 g*  of  powdered  zinc 
chloride  added.  The  ether  was  cooled  in' an  ice  bath,  and  dry  hydro 
gen  chloride  passed  in  until  the  ether  was  saturated.  The  flash 
was  then  allowed  to  stand  overnight.  A white  precipitate  formed, 
and  after  ten  hours,  there  seemed  to  be  no  more  deposit  forming. 
The  ether  was  decanted,  and  the  solid  washed  with  dry  ether.  It 
was  then  treated  with  £0  cc.  of  water,  warmed  to  50°,  and  cooled 
immediately.  An  oil  layer  formed,  but  it  did  not  crystallize,  even 
when  dissolved  in  hot  toluene  and  cooled.  The  mixture  was  there- 
fore heated  on  a steam  cone  for  one  hour, until  the  oil  had  com- 
pletely gone  into  solution,  and  did  not  reappear  on  cooling.  To 
make  sure  that  the  lactone  was  converted  into  the  acid,  ammonia 
was  added  until  the  solution  reacted  neutral  to  litmus,  and  it 
was  boiled  for  several  minutes  with  boneblach,  filtered,  acidified 
and  cooled  in  an  ice  bath  for  several  hours.  Crystals  separated, 
and  a portion  melted  at  77-8E0.  The  first  fraction  weighed  1.3  g. 
The  water  was  evaporated  down  about  half  way,  and  chilled  again, 
when  .9  g.  more  of  solid  separated.  This  solid,  on  recrystalliza- 
tion melted  at  82-84.5°.  It  was  partly  soluble  in  sodium  carbonate 
and  to  dissolve  out  all  the  soluble  portion,  it  was  mixed  with 
excess  sodium  carbonate  and  filtered.  The  insoluble  portion  was 
reeryStall ized  from  water,  and  it  melted  at  138.5-141°,  .7  g. 
being  obtained.  As  this  was  not  enough  to  purify  further,  it  was 
analyzed  directly. 


. 


37. 

Analysis:  Subst.  .3923  g.  CO^  .9641  g.  H^O  .1934  g. 

Calculated  C 67.4%  H 5.6% 

Found  C 67.01%  H 5.5% 

The  sample  analyzed  was  contaminated  so  that  it  appeared 
pink,  hut  some  ox  the  crystals,  when  held  up  to  the  light,  were 
color le ss • 

The  sodium  carbonate  solution  was  acidifed  with  hydro- 
chloric acid,  whereupon  a considerable  portion  of  an  oil  separated. 
This  was  removed  by  filtration,  and  the  water  was  allowed  to  stand. 

After  24  hours,  brown,  cubical  crystals  had  formed.  They  melted 
o 

at  140-142  . ivlixed  with  the  5-methyl  7-hydrcxy  chromanone-2  which 
was  analyzed,  they  melted  at  14U-141.50. 

Since  no  2-4-dihydr oxy  6-methyl  ^-phenylpropionic  acid 
could  be  isolated  in  this  reaction,  it  was  concluded  that  the  free 
acid  was  unstable,  and  closed  spontaneously  to  give  the  lactone. 

E.  CONDENSATIONS  OF  NITRILES  WITH  PHLOROGLUCINOL. 

1.  Condensation  of  phi oro glue inol  with  ^-chlorpropio- 
nitrile. 

Five  grams  of  pure  phloroglucinol , which  had  been  dried 
at  120°  for  1 1/2  hours,  and  5 g.  of  ^-chlorpropionitrile  were 
dissolved  in  100  cc«  of  dry  ether,  and  4 g»  of  powdered  zinc 
chloride  were  added.  The  flash  was  cooled  with  ice,  and  dry  hydro- 
gen chloride  was  passed  in  until  the  solution  was  saturated.  A 
brov/n  liquid  separated  in  the  bottom  of  the  flash,  and  after 
standing  for  about  one  hour,  it  began  to  solidify . The  flask  was 
allowed  to  stand  for  20  hours,  when  most  of  the  liquid  had  solidi- 


38 


fied.  The  ether  was  decanted,  and  the  residue  washed  with  dry  ether. 

o 

It  was  then  treated  with  20  cc.  of  water,  warmed  to  about  40  for 
5 minutes,  and  then  cooled.  No  oil  layer  separated.  After  standing 
for  24  hours, it  was  extracted  twice  with  butyl  alcohol,  the  butyl 
alcohol  washed  once  with  water,  and  the  wash  water  extracted  again 
with  butyl  alcohol.  Th  water  was  colorless,  and  was  discarded. 

The  butyl  alcohol  was  distilled  off  under  vacuum,  when  about  10- 
12  g.  of  dark  brown  liquid  remained.  This  was  taken  up  in  150  cc. 
of  boiling  water,  heated  to  boiling  until  all  of  the  butyl  alcohol 
was  removed,  bone-blaclied,  and  filtered.  The  filtrate  was  light 
colored,  and  from  it  there  separated  about  5 g«  of  a viscous  oil. 
This  failed  to  crystallize  on  standing  for  one  week.  When  it  was 
placed  in  a dessicator  and  allowed  to  dry  thoroughly,  the  oil 
became  glassy,  and  could  not  be  purified. 

The  oil  was  very  soluble  in  sodium  carbonate,  and  upon  j 
acidification,  came  out  again  as  an  oil.  Numerous  attempts  were 
made  to  prepare  derivatives  of  the  oil,  such  as  derivatives  with 
phenyl  isocyanate,  diphenyl  carbamine  chloride,  and  the  lead  salt. 
The  two  former  condensation  products  came  out  as  oils,  and  the 
lead  salt  did  not  analyze  for  any  definite  compound.  In  addition, 
attempts  were  made  to  prepare  an  acetate,  and  a benzoate  of  the  oil. 
The  acetate  could  not  be  purified,  and  the  benzoate  could  not  be 
isolated,  as  the  acid  group  which  was  present  made  it  soluble  in 
alkali,  and  upon  treating  the  compound  with  boiling  water  to  remove 
the  benzoic  acid,  the  derivative  was  saponified,  and  there  fore 
could  not  be  isolated. 

In  order  to  compare  the  product  obtained  in  this  con- 
densation with  that  obtained  from  acrylic  nitrile,  a reaction  was 


I 


. 


39. 


run  with  these  two  substances. 

2.  Condensation  of  phloroglucinol  with  acrylic  nitrile. 

In  100  ce.  dry  ether  were  dissolved  4,5  g.  of  dry  phlor 
oglueinol,  and  2.2  g.  of  acrylic  nitrile.  There  were  added  2 g.  of 
powdered  zinc  chloride,  and  the  ether  cooled  in  ice,  while  a strea; 
of  hydrogen  chloride  was  passed  in.  An  instant  turbidity  occurred, 
followed  by  the  separation  of  a liquid  layer.  On  standing  overnigh 
the  liquid  in  the  bottom  of  the  flask  had  entirely  solidified.  The  j 
ether  was  decanted,  the  product  washed  with  ether,  and  then  t reate 
with  20  cc-  of  water.  It  dissolved  and  did  not  come  out  again  on 
cooling. 

The  water  solution  was  extracted  with  butyl  alcohol, 
and  the  alcohol  was  distilled  off  under  vacuum.  A brown  glassy 
liquid  was  obtained,  but  it  failed  to  crystallize.  The  weight  of 
the  product  was  estimated  at  5 grams.  It  was  boiled  up  with  100  cc 
of  water,  boneblaeked,  filtered,  and  the  solution  chilled  to  zero 

o 

degrees.  A solid  separated,  and  a portion  of  it  melted  at  130-132  . 
The  yield  was  1.5  g. 

The  solid  was  crystallized  once  from  water,  after  which 

o o 

it  sintered  at  134-135  , and  melted  at  139-140  . As  there  was  not 
enough  of  it  obtained  for  further  purification,  it  was  analyzed. 
Analysis:  Subst.  .2612  g.  C0g  .5799  g.  H^O  .1631  g. 

Gal.  G9Hq0  C 60. 0$  H 4.4% 

Pound  C 60.5%  H 6.2% 

This  analysis  was  not  accepted  as  a good  analysis,  as 
a certain  amount  of  volatile  copper  salts  blew  into  the  sulfuric 


. 


. 


40. 


acid,  which  accounts  for  the  high  result  for  hydrogen.  However,  as 
there  was  not  enough  of  the  substance  at  hand  to  be  analyzed  again, 
this  reaction  will  have  to  be  repeated. 

3.  Condensation  of  phlorogluc inol  with  y-chlorbutyro- 
nitrile . 

A condensation,  identical  with  the  ones  already  described 
was  run  with  5 g.  of  7-chlorbutyronitrile  and  5 g.  of  phloroglu- 
cinol.  The  reaction  mixture  was  allowed  to  stand  for  six  days.  The 
residue,  after  the  decantation  of  the  ether,  was  treated  v/ith  20 
cc.  of  water,  and  heated  on  a steam  bath  for  three  hours.  The  flask 
was  cooled  in  ice,  when  a brown  solid  separated.  It  was  filtered 
off,  washed  with  water,  and  dried.  The  compound  was  stable  at  245°, 
and  was  readily  soluble  in  cold  sodium  carbonate.  On  acidification 
of  the  alkaline  solution,  the  compound  was  thrown  out  again, 
although  it  crystallized  slowly.  Owing  to  the  lack  of  time,  an 
analysis  of  this  compound  has  not  been  made  to  date.  Yield  2.5  g. 

F.  OTHER  CONDENSATIONS  ATTEMPTED. 

Attempts  were  made  to  condense  in  the  same  manner  as  has 
been  already  described  for  nitriles,  other  halogen  compounds  with 
resorcinol.  The  principal  ones  tried  were  ethylene  dibromide, 
trimethylene  bromide,  chloracetic  ester,  ^-chlorpropionic  ester, 
and  allyl  bromide.  Only  in  the  case  of  allyl  bromide  was  any 
product  at  all  obtained,  and  in  this  case.,  there  separated  .6  g. 
of  a solid  which  melted  from  167-175°,  from  10  g.  of  resorcinol 
and  12  g.  of  allyl  bromide.  This  experiment  was  therefore  repeated 
a larger  amount  of  reagents  being  used,  and  a longer  time  being 


. 


41. 


allowed  for  the  condensation,  hut  again  only  a very  snail  amount  of 
solid  was  obtained.  This  was  not  worked  up  further. 

An  attempt  was  made  to  condense  phenol  with  ^-chlorpro- 
pionitrile,  but  there  was  no  evidence  of  a reaction  taking  place. 
The  ether  solution  was  allowed  to  stand  for  twenty  four  hours,  and 
the  ether  was  removed  by  distillation.  Out  of  10  g.  of  yS-chlor- 
propionitrile  used  there  were  recovered  9 g.  unchanged. 

In  an  identical  manner,  a condensation  between  2-4- 
dihydroxy  p-phenylpropionie  acid  and  ^>-chlorpropionitr ile  was  tried 
There  was  recovered  from  the  reaction  mixture  a large  proportion  of 
the  acid  unchanged,  and  in  addition,  some  of  the  corresponding 
lactone,  or  7-hydroxy  chromanone -2. 

V.  SUMAHY. 

The  reaction  of  certain  nitriles  with  phenols  has  been 
studied,  and  found  t o be  unlike  the  reactions  secured  by  Hoesch. 
Instead  of  ketones,  there  have  been  isolated  nitriles,  lactones, 

and  acids. 

The  reaction  of  nitriles  with  phenols  under  the  condi- 
tions studied  has  been  shown  to  be  limited  to  compounds  from 
which  water  can  not  be  readily  eliminated. 

It  has  been  shown  that  the  nitriles  used  do  not  condense 
with  phenol  itself  under  the  same  conditions  that  were  used  for 
polyhydroxy  phenols. 

The  mechanism  of  the  Hoesch  reaction  has  been  proved. 

An  attempt  has  been  made  to  generalize  the  reaction  of 
aliphatic  halides  with  phenols. 


. 


42. 


A convenient  method  for  the  preparation  o 
phenolic  acids  has  been  found. 


f certain 


43. 


VI. 

BIBLIOGRAPHY. 

(1) 

Perkin  and 

Robins  on 

J.C.S.  93,  489,  517  (1908) 

(2) 

Kostanecki 

and  Lampe 

Ber.  31,  784  (1904) 

(3) 

Bistrzycki 

Ber.  31,  2812,  (1898) 

(4) 

Simonis 

Ber.  31,'  2821,  (1898) 

(5) 

Dimroth 

Ber.  35,  993,  (1902) 

(6) 

Ueyer 

J.  Pr.  Ch.  67,  342  (1903) 

( 7 ) 

Gatterman 

Ann.  357,  318,  (1907) 

(8) 

Hoesch 

Ber.  48,  1122,  (1915) 
Ber.  50,  462,(1917) 

(9) 

Tr8ger  and 

nilning 

ti.Pr.Ch.  ii,  69.,  347,  (1904). 

(10) 

Ghosh 

J.C.S.  109,  105,  (1916) 

(11 ) 

Sonn 

Ber.  50,  462,  (1917) 

Ber.  50,  1262,  (1917) 

Ber.  51,  821,  1829,  (1918) 
Ber.  52,  923,  11919) 

(12) 

Bargellini 

and  Forli 

-Forti 

GeZz.  Chim.  Ital.  41,  I,  747,  (1911 

(.13  ) 

Slater  and 

Stephen 

J.C.S.  117.  309,  (1920) 

(14) 

Stephen 

J.C.S.  117,  1529,  (1920) 

(15) 

Clai sen 

Ann.  401,  21,(1913) 
Ann.  418,  69,  (1919) 

(16) 

Adams  and 

Powell 

J.A.C.S.  42,  646,  (192o) 

(17) 

Karrer 

Helv.  Chim.  Acta  I_I,  89,  462,  486 
(1919).  Ill,  261,  392,  541,  (1920). 
IV.  203,  707,  (1921) 

(18) 

Fischer  and  Nouri 

Ber.  50,  611,  693,  (1917) 

(19) 

Bauer  and 

Schoder 

Arch,  der  Phar.  259 . 53,  (1921) 

44. 


( £0 ) Moureu  Bull.  Soc.  Chim.  27_,  901,  1 192u  ) 

(21)  Gabriel  Ber.  23,  1771,  (1890) 

(22)  Hlasiwetz  and  Grabov/ski 

Ann.  159.  102,  (1866 ) 

(23)  W.  Will  Ber.  16,  2116,  (1883) 

(£4)  von  Pechmann  Ber.  17^,  932,  (1884) 


VITA. 


The  writer  was  horn  in  Charleston,  South  Carolina,  on 
January  7,  1895.  At  the  age  of  nine  years,  he  moved  to  Schenectady, 
New  York,  where  he  completed  his  grammar  and  high  school  education. 
He  entered  Wesleyan  University,  Middletown,  Connecticut,  with  the 
class  of  1918,  and  secured  the  degree  of  Bachelor  of  Science  in 
that  year.  He  completed  one  year  of  graduate  study  at  the  same 
institution,  and  received  the  degree  of  Piaster  of  Science  in  1919. 
He  has  since  been  a graduate  student  at  the  University  of  Illinois. 
His  teaching  appointments  have  been  as  follows. 

1919- 20  Graduate  Assistant  in  Chemistry. 

1920- 21  Assistant  in  Chemistry. 

1921- 22  (1st  semester)  Graduate  Assistant  in  Chemistry. 


